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Alzheimer's & Dementia : the Journal of... Feb 2024We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological...
INTRODUCTION
We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs).
METHODS
We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions.
RESULTS
We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.
Topics: Mice; Humans; Animals; Apolipoprotein E4; Heparan Sulfate Proteoglycans; Phosphorylation; Apolipoproteins E; Alzheimer Disease; Immunologic Factors; Apolipoprotein E3
PubMed: 37791598
DOI: 10.1002/alz.13436 -
Cancer Science Jun 2023
Topics: Humans; Follow-Up Studies; Rituximab; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Etoposide; Doxorubicin; Prednisone; Vincristine; Lymphoma, Large B-Cell, Diffuse
PubMed: 36929591
DOI: 10.1111/cas.15784 -
International Journal of Molecular... Nov 2023With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral... (Review)
Review
With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.
Topics: Humans; Neurodegenerative Diseases; Amyotrophic Lateral Sclerosis; Parkinson Disease; Alzheimer Disease; Biomarkers
PubMed: 38003309
DOI: 10.3390/ijms242216119 -
Cancers Jun 2023Despite the widespread use of combined antiretroviral therapy (cART) and the subsequent decrease in AIDS-defining cancers, HIV-related lymphomas remain a leading cause... (Review)
Review
Despite the widespread use of combined antiretroviral therapy (cART) and the subsequent decrease in AIDS-defining cancers, HIV-related lymphomas remain a leading cause of morbidity and mortality in people with HIV (PWH). Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype in PWH. This lymphoma is a heterogeneous disease including morphological variants and molecular subtypes according to the cell of origin or the mutation profile. In the pre-cART era, treatment with standard-dose chemotherapy induced high rates of toxicity and outcomes were very poor. The introduction of cART and the incorporation of infection prophylaxis allowed the use of conventional intensive chemotherapy regimens used in the general population, such as R-CHOP or R-EPOCH. The use of cART during chemotherapy treatment was initially controversial due to the potential risk of adverse drug-drug interactions. However, the availability of current cART regimens with less potential to cause drug interactions and evidence that cART improves survival rates in NHL strongly support the use of cART in PWH with DLBCL. Consequently, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PWH with NHL.
PubMed: 37370801
DOI: 10.3390/cancers15123191 -
Molecules (Basel, Switzerland) Jun 2023Cancer continues to pose a severe threat to global health, making pursuing effective treatments more critical than ever. Traditional therapies, although pivotal in... (Review)
Review
Cancer continues to pose a severe threat to global health, making pursuing effective treatments more critical than ever. Traditional therapies, although pivotal in managing cancer, encounter considerable challenges, including drug resistance, poor drug solubility, and difficulties targeting tumors, specifically limiting their overall efficacy. Nanomedicine's application in cancer therapy signals a new epoch, distinguished by the improvement of the specificity, efficacy, and tolerability of cancer treatments. This review explores the mechanisms and advantages of nanoparticle-mediated drug delivery, highlighting passive and active targeting strategies. Furthermore, it explores the transformative potential of nanomedicine in tumor therapeutics, delving into its applications across various treatment modalities, including surgery, chemotherapy, immunotherapy, radiotherapy, photodynamic and photothermal therapy, gene therapy, as well as tumor diagnosis and imaging. Meanwhile, the outlook of nanomedicine in tumor therapeutics is discussed, emphasizing the need for addressing toxicity concerns, improving drug delivery strategies, enhancing carrier stability and controlled release, simplifying nano-design, and exploring novel manufacturing technologies. Overall, integrating nanomedicine in cancer treatment holds immense potential for revolutionizing cancer therapeutics and improving patient outcomes.
Topics: Humans; Nanomedicine; Neoplasms; Drug Delivery Systems; Immunotherapy; Diagnostic Imaging; Nanoparticles
PubMed: 37446806
DOI: 10.3390/molecules28135145 -
Frontiers in Chemistry 2024The epoch of Nano-biomaterials and their application in the field of medicine and dentistry has been long-lived. The application of nanotechnology is extensively used in... (Review)
Review
The epoch of Nano-biomaterials and their application in the field of medicine and dentistry has been long-lived. The application of nanotechnology is extensively used in diagnosis and treatment aspects of oral diseases. The nanomaterials and its structures are being widely involved in the production of medicines and drugs used for the treatment of oral diseases like periodontitis, oral carcinoma, etc. and helps in maintaining the longevity of oral health. Chitosan is a naturally occurring biopolymer derived from chitin which is seen commonly in arthropods. Chitosan nanoparticles are the latest in the trend of nanoparticles used in dentistry and are becoming the most wanted biopolymer for use toward therapeutic interventions. Literature search has also shown that chitosan nanoparticles have anti-tumor effects. This review highlights the various aspects of chitosan nanoparticles and their implications in dentistry.
PubMed: 38660569
DOI: 10.3389/fchem.2024.1362482 -
Frontiers in Neurology 2023Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated...
BACKGROUND
Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods.
OBJECTIVE
The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry.
METHODS
In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect.
RESULTS
Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006).
CONCLUSION
Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.
PubMed: 38187157
DOI: 10.3389/fneur.2023.1274194 -
Blood Advances Jun 2023The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone... (Clinical Trial)
Clinical Trial
The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Etoposide; Lymphoma, Large B-Cell, Diffuse; Prednisone; Prospective Studies; Rituximab; Vincristine
PubMed: 36521030
DOI: 10.1182/bloodadvances.2022009145 -
Blood Advances Nov 2023In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified...
In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
Topics: Humans; Middle Aged; Rituximab; Retrospective Studies; Lymphoma, Large B-Cell, Diffuse; Prednisone; Vincristine; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Cyclophosphamide; Doxorubicin; Etoposide; Lactate Dehydrogenases
PubMed: 37171397
DOI: 10.1182/bloodadvances.2023009731 -
Stroke Dec 2023The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop... (Review)
Review
The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop brought together representatives from academia, industry, and government representatives. The discussion examined approaches in 4 epochs: pre-reperfusion, reperfusion, post-reperfusion, and access to acute stroke interventions. The participants identified areas of priority for developing new and existing treatments and approaches to improve stroke outcomes. Although many advances in acute stroke therapy have been achieved, more work is necessary for reperfusion therapies to benefit the most possible patients. Prioritization of promising approaches should help guide the use of resources and investigator efforts.
Topics: Humans; Brain Ischemia; Thrombolytic Therapy; Stroke; Thrombectomy; Reperfusion; Treatment Outcome
PubMed: 37886850
DOI: 10.1161/STROKEAHA.123.044279